Bioequivalence and Bioavailability Forum

Hi Mac,

❝ "Additional Comments: This drug product is designed to provide both a quick onset and prolonged action. Please ensure that the Tmax (time to peak plasma naproxen concentrations) is comparable between the test and reference products."

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❝ What does "comparable" mean? Is this a qualitative comparison or an important criterium that needs to be statistically analysed?

These are interesting questions! On different occasions the FDA pointed out that sometimes reviewers “look” at t_max – though not mentioned the general BE guidance (and in the recent draft as well). No idea what looking means. Maybe something similar to the ambiguous statement in EMA’s GL?

[…] if rapid release is claimed to be clinically relevant and of importance for onset of action or is related to adverse events, there should be no apparent difference in median t_max and its vari­abi­lity between test and reference product.

What’s “no apparent difference” and how to compare “its variability”? Box plots?

❝ […] what would be the best way to do this?

If you want to perform a formal test, nonparametric statistics^1,2 (of untransformed data) are manda­tory, since t_max is sampled from a discrete distribution.*

❝ One way would be to do partial AUCs, for example AUC0-Tmax and AUCTmax-t and have those pass the 80-125 criterium. Is this necessary?

I don’t think so, since the FDA specifically asks for t_max and not for partial AUCs. The truncation time-points (early onset and prolonged action) for other ER drugs (methylphendiate and zolpidem) are based on pharmacodynamics (not the reference’s median t_max used for early exposure). I’m not aware whether such data exists for ER naproxen.

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1. Koch GG. The Use of Non-Parametric Methods in the Statistical Analysis of the Two-Period Change-Over Design. Biometrics. 1972;28(2): 578–85.
   
2. Steinijans VW, D Hauschke D. Update on the statistical analysis of bioequivalence studies. Int J Clin Pharm Ther Toxicol. 1992;30 Suppl 1:S45–50.

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• Nonparametric testing of t_max (if clinically relevant) was mandatory in the EU before 2010 – and still is in other regulations. Since nonparametrics gave EMA the creeps, testing was replaced in the current GL by the vague statement given above.